This project is aimed at testing the hypothesis that alterations in calcium regulatory hormones and serum calcium/phosphate (Ca/PO4) homeostasis, are directly related to the etiology/pathogenesis of Alzheimer's Disease in humans. The effects of altered serum Ca/PO4 regulation on the brain could occur through chronically altered brain PO4/Ca homeostasis, through direct impact of altered peripheral hormonal patterns of actions on brain neurons (which contain vitamin D, calcitonin, glucocorticoid, and parathyroid hormone (PTH) receptors, or they may occur through aging-associated changes in Ca regulation or hormonal sensitivity at the level of the brain neuron. One interesting pathway in this context, involves the possibility that cerebral energy metabolism may be altered, possibly due to chronic subclinical hypophosphatemia and resulting hypoxia, which in turn could result in impaired Ca buffering and brain cell loss. The experimental goals of this project are few in number and relatively straightforward. However, each will be extremely time-consuming. These are to: 1) Study subjects in the very earliest stages of AD in a prospective longitudinal study that will test peripheral Ca regulation, endocrine function and cerebral energy metabolism and relate these to the onset and progression of AD over two years. Measurements will be made of the responsiveness and efficacy of four major Ca regulatory hormones (Vitamin D metabolites, adrenal-pituitary hormones, PTH and calcitonin) in relation to neuropsychological tests and magnetic resonance tests (MRI). 2) Conduct an experimental intervention test in humans diagnosed with probable AD by NIA-NINDS criteria, using a Ca regulatory hormonal treatment (1,25(OH)2-D) that is considered sufficiently safe for chronic human experimentation. Treatment would be for two years, and assessment would be by neuropsychological tests and MRI. Even partly positive results of these studies would hold major potential for both new therapeutic and new early diagnostic approaches to the problem of Alzheimer's disease.